1. Field of the Invention
The present invention is directed to the fields of disease therapy, cancer biology, and cancer therapy. More specifically, the present invention is directed to providing local regional treatment in an individual in situ by administering a polymer and a cross-linking agent. More preferably, the local regional treatment in situ is of a tumor in the individual.
2. Description of Related Art
Systemic administration of anticancer agents often results in severe dose-limiting toxic effects. Therefore, site-specific delivery of anticancer drugs, such as in local regional therapy, is extremely beneficial for solid tumors. During local regional therapy for treatments of tumors, current methods include transcatheter arterial chemoembolization (TACE), brachytherapy, and peritumor/intralesional injection. Patients with malignancies which are inoperable or unsuitable for surgery often have a poor prognosis, and current palliative treatments have an associated morbidity and mortality.
Primary and metastatic tumors may receive their blood supply predominantly or entirely from the arteries. TACE with various kinds of anticancer drugs has been considered an effective method of treating unresectable primary tumors and metastases. The potential therapeutic effect results from the combination of embolic occlusion of the blood supply to the neoplasms and local retention of the infused chemotherapeutic drugs. Agents currently used to achieve vascular occlusion include, for example, lipiodol (iodized oil). However, conventional TACE has some disadvantages. Specifically, materials currently used for chemoembiolization, i.e., particles and lipid, occlude tumor vessels incompletely. Intraorgan collateral vessels rapidly develop around the occlusions, and effective dearterialization of the organ may be difficult to achieve even after repeated embolization. For example, it is known that shortly after hepatic vessels were embolized with Gelfoam powder, portions of the intrahepatic arteries in various parts of the liver were reconstituted via microcollaterals. Although lipiodal chemoembolization has been considered the most effective of these methods, on the basis of reports of a decrease in tumor size in a nonrandomized trial, the embolization effect is questionable. One study suggested that lipiodal has no thromboembolic effect. There was no statistically significant difference in tissue necrosis in lipiodol-injected hepatocellular carcinoma versus noninjected controls. Repeated peripheral embolization of the hepatic artery with very small particles can cause occlusion of the collateral vessels as well as the primary hepatic artery, but this might well result in necrosis of normal tissue as well as tumor in patients whose metastases are being embolized. In addition, complications are frequent and side effects have been reported.
Tumor vascularity has been identified as a prominent prognostic factor for patients receiving regional chemotherapy of tumors given that multiple prognostic factors for survival are related both to growth of the tumor. Presumably, particles and lipid drops cause discontinuous embolization of tumor vessels, since unoccluded microcirculation of collateral vessels may continue to supply the tumor cells. Therefore, to overcome the problem of conventional TACE, a better strategy to improve cancer therapy by TACE should include complete occlusion of tumor vessels, damaging normal tissue as little as possible, and preventing the formation of collaterals.
Tumor therapy also includes utilization of irradiation of a tumor for eradication purposes. Brachytherapy methods utilize small particles or seeds of radioactivity implanted into a tumor and are used often in cervical, breast, endometrial, prostate, and head and neck cancers. However, current brachytherapy seed-dispensing methods dictate less than desirable loading yields, are more expensive, are cumbersome to administer, and render a less than ideal treatment response.
In another technology requiring surgical intervention, patients with operable brain tumors, such as glioblastoma multiforme, are subjected to tumor removal through surgical means, and GLIADEL® (Nova Pharmaceutical Corporation; Baltimore, Md.) biodegradable wafers made of a polyanhydride, such as polifeprosan 20, containing a chemotherapeutic are inserted into the remaining cavity. However, this method requires surgical removal of the tumor, which is not always feasible.
Peritumor/intralesional injection is another method in the art for administering a chemotherapeutic drug to a tumor. Numerous examples exist in the art wherein a chemotherapeutic is administered intratumorally in a gel as a sustained-release delivery system, such as an epinephrine (epi) gel (Miller et al., 1997; Burris et al., 1998; Kraus et al., 1998; Harbord et al., 1999; Ning et al., 1999; Smith et al., 1999; Monga et al., 2000). Alternatively, polymers are utilized as slow-release matrices including, for instance, a blend of copolymers (Jackson et al., 2000). However, these sustained release delivery systems administered by direct injection are subject to leakage into surrounding tissues in the absence of an agent, such as a cross-linking agent, or other means to retain the chemotherapeutic within the tumor itself.
Chinese Patent No. 1252310 is directed to a preparation having a medicine powder with a gel and cross-linked by, for example, calcium for local injection treatment and artery embolism treatment. However, the preparation is generated outside the body and not in situ in the tumor. Similarly, although Japanese Patent No. 10236984 regards a fibrin-containing composition for sustained release of a medical component and Japanese Patent No. 7097401 is directed to a bridged hyaluronic acid as a sustained-release preparation or an embolizing agent, neither patent concerns generation of the medicinal component/preparations within a tumor. Furthermore, none of the methods or polymer compositions in these patents utilize radionuclides as therapeutic agents.
U.S. Pat. No. 5,257,970 regards encapsulation of a drug in a liposome, injection of a photosensitizer into a host, injection of the liposome-encapsulated preparation systemically, and heating of a tumor to melt the liposome to allow mixing of the activation components.
Downs et al. (1992) use calcium alginate beads as a slow-release system of administering growth factors. However, the growth factor/sodium alginate compositions were created and uniform beads were obtained ex vivo by passing the mixture of beads through a syringe. This process is cumbersome and generates significant loss of therapeutic material, which can be costly.
Kitazawa et al. (1997) utilize a fibrin glue as a drug carrier for the chemotherapeutic doxorubicin and determine there is an improvement in sustained release in the presence of sodium alginate. Again, the fibrin (fibrinogen) sodium alginate powder was generated outside of the body of the tumor-bearing rats.
PCT Application WO 00/00222 is directed to sustained release of pharmaceutical compositions with a thermosensitive, biodegradable hydrogel consisting of a block copolymer of poly(d,1-1-lactic acid) or poly(lactide-co-glycolide) and polyethylene glycol. The polymerix matrix containing the pharmaceutical concentration is injected into the tumor to create a gel in vivo. However, the gel formation is temperature-activated and generates only after sufficient time to reach the required temperature, thereby permitting leakage into surrounding tissues in the meantime. PCT Application WO 00/38651 concerns a similar technology further comprising pH-responsive gelation/degelation properties.
U.S. Pat. Nos. 6,004,573; 6,117,949; and 5,702,717 are directed to a injectable biodegradable polymeric liquid matrix containing a drug which becomes a gelatinous composition after it reaches body temperature.
Thus, the absence in the art of a method to administer in situ an anticancer drug with high loading yields for a drug carrier, absence of leakage into surrounding tissues, lower cost, ease of process and better treatment response is fulfilled with the methods of the present invention.